Cytokines are a unique family of growth factors. They act as endogenous mediators that coordinate inflammatory signaling (Romagnani S., Ann Allergy Asthma Immunol. 2000, 85: 9-21).
Pro-inflammatory cytokines (e.g., TNF-α and interleukins 1β, 2, and 8), produced predominantly by activated macrophages, trigger inflammatory response to exogenous pathogens. However, their overproduction is detrimental to vital organs. Anti-inflammatory cytokines (e.g., interleukins 4 and 10) cease or attenuate inflammatory progression so as to retain the functions of vital organs (Taniguchi et al., Crit. Care Med. 1999, 27: 1262-1264; and Kasai et al., Res. Commun. Mol. Pathol. Pharmacol. 1997, 98: 34-4220).
Production of pro-inflammatory and anti-inflammatory cytokines is stringently regulated via complicated mechanisms. Imbalanced production of the two cytokines results in many diseases, e.g., arthritis, renal disease, bone abnormalities, asthma, cancer, sepsis, neurodegeneration, neutrophilic alveolitis, hepatitis, ischemia/reperfiision, and inflammatory bowel disease (Taniguchi et al., Crit. Care Med. 1999, 27: 1262-1264; and Kasai et al., Re,s Commun. Mol. Pathol. Pharmacol. 1997, 98: 34-42).
NF-κB is a transcriptional factor that mediates cytokine release and plays a key role in modulating inflammatory response. It is a potential target for treating diseases, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis psoriasis, asthma, septic shock, autoimmune diseases (e.g., systemic lupus erythromatus), neurodegeneration, atherosclerosis, oncogenesis, ataxia telangiectasia, lung diseases (e.g., ARDS, systemic inflammatory response syndrome, respiratory viral infections, occupational and environmental lung disease, cystic fibrosis, idiopathic pulmonary fibrosis, primary pulmonary hypertension), HIV, and influenza (Kristman J W., et al., Chest 2000, 117: 1482-1487; and Baldwin, A S. Jr., Annu. Rev. Immunol. 1996, 14: 649-683).